3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Situation analysis of drug supply management in Tshwane.(2003-12-18) Mubangizi., Deusdedit, Katetegirwe.Tshwane is one of three metropolitan municipalities in Gauteng Province and a cross border district with North West Province. Tshwane has a complex Drug Supply Management system. Gauteng Provincial Authority (GPA), North West Provincial Authority (NWPA) and City of Tshwane Metropolitan Municipality (CTMM) play significant roles. This has resulted in duplication of duties and inefficient use of resources. The aim of the study was to describe the current Drug Supply Management System in Tshwane, identify any weaknesses plus the factors responsible for the observed weaknesses and formulate recommendations for improvement.Item Formulation of a natural intraoral dispersible film (IDF) for intraoral delivery of various natural drugs using edible rice paper film as the carrier vehicle(2016) Eliphaz, MukasaBackground and the purpose of study. At present, pharmaceutical researchers are focusing on instantaneous intraoral dispersible technologies as novel drug delivery systems because; they have outstanding advantages over the traditional oral and parenteral routes of drug administration. Some essential natural drugs have low oral bioavailability due to extensive first pass metabolism and pre systemic degradation in the gastrointestinal tract. Aim. Now, a cheap rice paper Intraoral Dispersible Film (IDF) has been developed Objectives. In this study, formulation was optimized using the experimental factorial design. The IDFs were loaded with model, natural, anti-cancer drugs, Resveratrol and Curcumin with low oral bioavailability. Methods. They were evaluated for thickness, folding endurance, swelling behaviour, among others. These related to their drug release properties. Permeation was evaluated using the pig mucosal membrane mounted on a Franz diffusion cell. Taste testing was done to determine acceptability using a taste panel. Results and Discussions. Sixteen formulations showed variations in their profiles. Formulation 16 proved optimal. The dissolution rate at steady state concentrations of Resveratrol was 29mg per second and the Permeability coefficient was 389 mg/sec.cm2. That of Curcumin was 0.25mg per second and the Permeability coefficient was 42.71 mg/sec.cm2 Resveratrol permeability rate was 0.42 mg/sec. and that of Curcumin was 0.14 mg/sec. Resveratrol Flux was 0.21 mg/sec./cm2. Curcumin Flux was 0.14 mg/sec. / cm2. Drug entrapment was 80% for both molecules. The 20 mg of Resveratrol and Curcumin would then dissolve in 47.6 sec. and 71.4 sec. respectively. In this study, after permeation, a concentration of 6.73mg/ml of Resveratrol and 0.061mg/ml of Curcumin were detected after 2 hours of the experiment on administering only 20 mg of each of the drugs suggesting that Curcumin is 100 times less permeable than Resveratrol. The release profile is a burst release. On contrast, Curcumin oral dose of 2 g/kg to rats yielded 1.35±0.23 μg/ml in 0.83 hours and in humans, the same dose either undetectable or extremely low (0.006±0.005 μg/ml after 1 hour. Two separate mono-glucuronide metabolites yielded Cmax ~7.5 μM following a single 5.0 g oral dosage of Resveratrol. Conclusion. The key finding is, ex vivo release profiles of the optimized formulation revealed first order release and later zero order. Therefore, it is evident that rice paper IDF could efficiently deliver natural drugs into the systemic circulation. However, later, further studies are needed to prove increased bioavailability to be performed in human subjectsItem Design of a depot formulation for disulfiram(2016) Mia, FatemaDrug addiction and abuse, specifically relating to alcohol, is a globally calamitous mental illness. An important facet of treating this destructive health issue is pharmacological intervention. The current treatment options and their limitations were reviewed as well as the advances that have been made in drug delivery technologies for combating addiction and abuse. The current treatment of addiction, and alcohol abuse in particular, is a large scale concern. Whilst treatment is available in the form of disulfiram, naltrexone and acamprosate; these too possess many short-comings. The greatest of which is poor compliance which results in relapse. This can be successfully averted by the utilisation of a feasible depot system to deliver the medication. Incorporation of disulfiram, an FDA-approved active with promising clinical potential, into a modified depot system comprising a dual delivery system yields a prospective solution to the drawbacks of current treatment regimes. The dual system is made up of nanomicelles dispersed within a thermosensitive gel. Immediate and sustained release is controlled by free disulfiram released into the gel and then the tissue and encapsulated disulfiram released from the nanomicelles into the gel and then the tissue, respectively. The thermosensitive gel is a carrier for the disulfiram-loaded nanomicelles and the free disulfiram. It also serves as a vehicle which allows ease of administration by maintaining a liquid state prior to intramuscular injection and thereafter solidifying into a solid gel-depot inside the muscle tissue. Polymers were selected based on the suitability to the desired outcome as well as compatibility with disulfiram. d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was used for nanomicelle formulation whilst Pluronic F127 (PF127) and high acyl gellan gum (HAGG) was chosen for the thermosensitive gel. A Face-Centred Central Composite Design was utilised for statistical optimization of the nanomicelles. The design consisted of two variables, 1) stirring time of the formulation (hours) and 2) the amount of TPGS used (mg), both of which were crucial to the success of the formation of the nanomicelles. Response surface and contour plots were generated for the variable effects on selected responses (i.e. drug entrapment efficiency, drug loading efficiency and drug release). Statistical optimization computed a single optimized formulation composed of 500mg TPGS and 1 hour of stirring. The optimized nanomicelles were then incorporated into the rheologically selected PF127-HAGG gel. The final nano-enclatherated-gel-composite (NEGC) underwent in vitro release testing, physicochemical characterization and physicomechanical characterization. Results displayed sustained release over 28 days with positive physicochemical and physicomechanical outcomes. Ex vivo results confirmed the release of disulfiram from the NEGC into the tissue as well as established the safety of the system through myotoxicity analysis. Administration of the NEGC to the Sprague-Dawley rat model determined the effectiveness and safety of the delivery system in vivo. Ultra Performance Liquid Chromatography was carried out on plasma to ascertain the level of disulfiram in the plasma. The NEGC yielded a maximum plasma level of 27.33g/mL which is above values previously reported. Ultrasound imaging confirmed the presence of the NEGC within the muscle over 28 days. Myotoxicity studies disclosed an increase in Creatine Kinase after administration with a return to normal levels within 24 hours indicating that permanent muscle damage did not occur. Histopathological lesions were symptomatic of injury and repair of tissue due to intramuscular needle insertion and the decline in lesion severity is indicative of mild, acute toxicity and repairable injury. The results obtained in this study revealed the therapeutic potential of the NEGC to treat not only alcohol addiction but perhaps other conditions as well due to the versatility of this dual delivery system.Item A dual oral intestinal film for pulsatile release of a mood stabilizing agent in the treatment of schizoaffective disorder(2016) Hoosain, Famida GhulamOral drug delivery is acknowledged by many as the idyllic method of drug delivery due to its versatility and convenience of administration. Nevertheless, the bioavailability of drugs delivered via the oral route remains disputed. Classically, conventional marketed drug delivery systems release drugs in inconstant and unpredictable manners, leading to sub-therapeutic and in some cases toxic drug doses. Consequently, patient compliance is compromised, in turn having an effect on the success of the therapeutic intervention in question. One such limitation occurs in the treatment of Schizophrenia, with patients unable to comply with treatment due to multiple administration requirements. Sulpiride, an antipsychotic agent, displays notable efficiency in reducing both positive and negative symptoms of Schizophrenia. However, sulpiride has a low bioavailability and thus therapy requires the use of large doses, and hence multiple administrations. In addition, a large percentage of Schizophrenic patients present with concomitant mood disorders, namely ‘Schizoaffective’ disorder, which further necessitates the use of mood stabilizing agents. As a result, patients end up with a huge pill burden and are unable to comply with therapy and this leads to reduced clinical outcomes. A dual layered, xerogel-bioadhesive intestinal patch drug delivery system (ODLS) was thus designed, formulated, and evaluated for the site-specific delivery of two bioactives in the treatment of Schizophrenia with concomitant mood disorders in a time controlled-idiosyncratic manner. Ultimately easing compliance to complicated treatment regimens, enhancing bioavailability and improving patient compliance. The ODLS essentially comprises of a bi-layered tablet, layer one comprised of a sustained release semi-interpenetrating polymer network (s-IPN) xerogel and a layer two of embedded pulsatile release bioadhesive intestinal patches, with the system as a whole enteric coated for protection. Intestinal patches encompassed in layer two are fabricated of a backing layer, a drug loaded layer, a mucoadhesive layer, and a mucus cleaving layer. The ODLS employs a combination of sustained and pulsatile drug release mechanisms, in addition to intestinal retentive mechanisms. Furthermore, the system physically protects the drug delivery system from acidic or proteolytic degradation within the human gastro-intestinal tract. The present study utilized the use of bioadhesion for site-specific and gastro retentive drug delivery, with crosslinking being employed for rate-modulated drug delivery. Sulpiride and sodium valproate were selected as model drugs for the sustained release xerogel layer and the pulsatile bioadhesive patch layer respectively in this study as sulpiride is an antipsychotic with low bioavailability yet good antipsychotic activity and sodium valproate is the mainstay drug treatment for mood disorders in schizophrenia. Therefore, sulpiride would profit from the sustained release as it would improve bioavailability and hence patient compliance, whereas sodium valproate would benefit from the pulsatile release so as to avoid the well-known resistance to therapy due to prolonged exposure to drug. Thus these drugs would gain benefit from the site-specific controlled drug delivery offered by the ODLS. The primary aim of the sustained release s-IPN xerogel was to ensure delayed release of drug over 24 hours thus decreasing the need for multiple administrations and to maintain a steady state drug concentration. Film casting, a versatile technique was utilized in the fabrication of polymeric films to develop the bioadhesive intestinal patches. Preliminary in vitro investigations led to identification of a combination of polymers and crosslinking agent best suited to develop the system. A central composite design was employed for system optimization. The xerogel layer demonstrated that zero-order drug release was achieved after the crosslinking procedure. Delayed drug release fundamentally decreases the number of doses required daily and thus patient compliance and clinical efficacy is improved. The pulsatile release layer displayed distinct triphasic drug release after assembly of the intestinal patches, pulsatile release of drugs fundamentally reduced resistance to drug therapy as well as reducing pill burden. Furthermore, in vitro analysis of the ODLS showed that the xerogel layer behaved superiorly in terms of controlling drug delivery in a site-specific and prolonged fashion in comparison to a marketed gold standard. There exists no gold standard for pulsatile delivery of sodium valproate hence the pulsatile layer was tested against the marketed standard administered as a single dose. In vitro findings were substantiated by in vivo analysis in a white pig model. Results indicated that the systemic bioavailability of sulpiride was higher than the gold standard and drug release was prolonged in a zero-order fashion over 24 hours. Sodium valproate released in a triphasic manner over 24 hours thus reducing the risk of treatment resistance and decreased pill burden. To summarize, the ODLS was able to overcome the many challenges associated with oral drug delivery in schizoaffective disorder, by simplification of complicated treatment regimens, and hence improving bioavailability of drug delivery orally. The benefits associated with oral drug delivery have evidently been exploited by the present study, producing a versatile drug delivery system which can successfully deliver two bioactives simultaneously via individualistic release patterns, thus treating both conditions with a single oral dosage form with a single daily administration.Item Novel variant for application as a prolonged release drug delivery system(2015) Kgesa, TebohoThe dissertation aims to discuss the disulphide and thiol chemistry for use in drug delivery. In particular it focuses on the use of the modified native ovalbumin polymer as a vehicle for the thiol containing captopril. The binding capabilities of thiols expand the area in which peptides and proteins can be used as potential therapeutic drug carriers. It is important that drug delivery systems enhance drug storage stability and in vivo particle stability while delivering the drug efficiently. As part of the developing novel drug delivery systems, thiol-based chemical reactions are distinctive role players in stabilizing disulphide bioconjugated nanostructures for use as efficient drug carrier vehicles in vivo. A review of the current approaches for designing, optimizing and functionalizing nanostructures and conjugates by thiol chemistry modifications was explored. Captopril (Cp) is an Angiotensin-Converting Enzyme (ACE) inhibitor, which acts as an anti-hypertensive, structurally contains a free reactive thiol that binds variably via the thiol/disulphide reaction. A single dose of captopril can regulate hypertension for up to eight hours and the duration of the antihypertensive action of a single dose of 35-75 mg would be taken at 8 hour intervals for 24 hours. Hence the necessities in developing a sustained controlled release ovalbumin carrier system to maintain relatively constant blood pressure levels for 24 hours. The research focused on the construction, characterization and optimization of the thiol conjugated complex for sustained oral drug delivery. The thiol/disulphide-functionalized captopril-ovalbumin conjugate complex was assessed in terms of the structural characteristics and the thiol-disulphide covalent substitution reaction. For analysis of the conjugation complex, the Fourier Transmission IR-spectroscopy (FTIR), H+ NMR and Differential Scanning Calorimetry (DSC) was performed and used to confirm conjugation. Preliminary studies focused on a comparative study of sodium alginate, polyvinyl alcohol and hydroxypropylmethylcellulose hydrogel formulations for the release testing and drug entrapment of the ovalbumin-captopril conjugate complex. Utilizing this data, a series of process variables were used to achieve an optimized formulation through a Box- Behnken statistical design. Furthermore the drug release profiles of the optimised formulation were then analyzed in vitro and in vivo. The captopril released from the formulation was high with a cumulative release of 82%. In vivo analysis was the final testing to verify the validity of the ovalbumin-captopril conjugate complex encapsulated in sodium alginate and utilized a pig model. Ultra Performance Liquid Chromatography (UPLC) blood analysis revealed increased blood levels of captopril (Cmax Cp=33.2ng/mL) in relation to conventional dosage forms validating prolonged (24 hour) site-specific release and increased bioavailability. In conclusion, our validated method was successfully applied to the pharmacokinetic studies of captopril in the blood plasma samples.Item An implantable nano-enabled bio-robotic intracranial device for targeted and prolonged drug delivery(2015-09-18) Mufamadi, Maluta StevenAlzheimer’s disease (AD) is the most prevalent and progressive neurodegenerative disorder (ND). It is characterized by a progressive decline of cognitive function, complete loss of memory, deterioration of visual capacity and the inability to function independently. According to the World Health Organization (WHO) it is estimated that about 26 million people suffer with AD worldwide. Although the etiology of AD is not fully understood, the aggregation of β-amyloidal (A) peptides that are associated with the formation of extracellular neurotoxin senile plaques and neurofibrillary tangles comprising hyperphosphorylated tau proteins have been recognized as the primary constituents that play a crucial role in AD. Several potential neurotherapeutic agents that can improve the management of AD such as metal chelators and alkaloid drugs have been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Metal chelators [e.g. histidine, Ethylenediaminetetraacetic acid (EDTA) and zinc acetate (ZnAc)] are the main therapy used for modulating Aβ peptide aggregation with biological metals (such as zinc and copper ions) which is associated with promoting neurotoxicity in AD. While alkaloid drugs, such as donepezil, galantamine and rivastigmine, are used to inhibit the enzyme acetylcholinesterase (AChE); memantine is used to block the N-methyl-D-aspartate (NMDA) receptors associated with pathological activation. Despite the availability of these indispensable drugs, the clinical utility of these drugs is hampered by their poor retention and difficulty in bypassing the highly restrictive Blood Brain Barrier (BBB). Therefore this study aimed at developing novel nanoliposomes (NLPs) surface-engineered with chelating and synthetic peptides that are capable of crossing the BBB thus improving delivery efficacy and modulating the extracellular neurotoxicity associated with β-Amyloid aggregates of AD. Furthermore, since this system was designed for a chronic condition, a temporary depot-based polymeric system was integrated for further enhancement of the liposomal half-life, storage and prolonged drug delivery over a period of 50 days. The surface-engineered NLPs produced were spherical in shape, 100-149±28nm ~ size, with a zeta potential range of -9.59 to -37.3mV and a polydispersity index (PdI) of 0.02-0.2. A Box-Behnken experimental design was employed for maximizing the ligand coupling efficiency (40-78%) and drug entrapment efficiency (DEE) that ranged from 42-79%. The optimized peptide-based ligand NLP formulation showed sustained drug release (30% of drug released within 48 hours). Chelating ligands on the surface of NLPs showed 50-68% modulation of neurotoxicity on PC12 neuronal cells induced by ZnAβ (1-42) or CuAβ (1-42) aggregates. When drug-loaded functionalized NLPs were embedded within the temporal hydrophilic hydrogel network/scaffold as an implantable nano-enabled bio-robotic intracranial device (BICD), the physicomechanical and physicochemical dynamics showed improvement of liposomal structure such as the stability, and homogeneity in distribution of the liposomes within the internal core of the hydrogel networks and post-lyophilized scaffold. In vitro studies in simulated cerebrospinal fluid (CSF) showed prolonged release behavior of the drug-loaded functionalized NLPs from the BICD with 50-70% released over 50 days. Scanning Electron Microscopy (SEM) and confocal microscopy confirmed intact liposomal structures within the temporal polymeric scaffold/depot post-fixation and post-lyophilization. Ex vivo studies confirmed cell proliferation and a low level of lactate dehydrogenase (LDH), which is associated with cell membrane damage/injury, after PC12 neuronal cells were exposed to the BICD. In addition, when PC12 neuronal cells were exposed to the BICD high accumulation of galantamine (GAL) into these PC12 neuronal cells was observed post-cultivation. This outcome indicated that the released drug-loaded functionalized NLPs from the BICD were still in their intact form and capable of serving as bio-robotic markers for the delivery of GAL into the neuronal cells in response to AD. Furthermore, intracellular activity validated that the synthetic peptide has the potency for targeted delivery of the drug-loaded NLPs post-release of the BICD in ex vivo studies. Overall, results from this study revealed that the BICD device had superior cytocompatibility and may be suitable for application as a prolonged and targeted delivery system for GAL into neuronal cells to treat AD.Item Development of versatile bio-stable oral polymeric delivery systems for proteins(2015) Kondiah, Pierre Pavan DemarcoAn oral proteomatrix drug delivery platform was formulated using pH responsive biostable polymers for slow release kinetics for the treatment of the neurodegenerative disease, multiple sclerosis (MS), which was the primary aim. After successful design and optimization for utilizing this system for MS, this system was further applied as a versatile platform for oral protein delivery. Interferon beta (INF- ) was selected as the oral treatment for MS. The fundamental effect of INF- in the treatment of MS is based on reducing the immune response that is directed against central nervous system myelin, i.e. the fatty sheath that surrounds and protects nerve fibers. Damage of nerve fibers, resulting in demyelination, consequently causes nerve impulses to be slowed or halted, thus producing symptoms of MS (Jongen et al., 2011). To date, INF- is effectively being used to treat MS subcutaneously or as intramuscular injections. These forms of administration have commonly been associated with multiple problems of pain, allergic reactions, poor patient compliance and chances of infection (Chiu et al., 2007). It was thus concluded to design an oral platform for the delivery of multiple protein therapeutic formulations. To prove the versatility of the proteomatrix system, two other demanding protein therapeutics for oral delivery, insulin and erythropoietin, were selected for further in vitro Box-Behnken series of formulations and in vivo analysis. By administration of these oral protein systems, a greater patient compliance can be achieved, thus enhancing the therapeutic profiles of patients with conditions of MS, diabetes and chronic renal failure resulting in chronic anemia. All studies consisted of in vitro drug release studies, characterization using specific analytical techniques for testing the mechanical properties, as well as the physicochemical characteristics of the copolymeric system. All proteins, INF- , insulin and erythropoietin, were analyzed in vivo using New Zealand White rabbits (NZW) with determination of the protein from serum obtained during regular blood sampling intervals.Item A bioactive association platform delivery system for enhanced efficacy of pharmaceutical products(2015) Braithwaite, Miles CharlesOral delivery of drugs is inundated by formulation challenges predominantly due to poor physicochemical properties of chemical entities resulting in anomalies in serum levels and inconsistent pharmacokinetics and pharmacodynamics. Similar challenges exist for nutraceutical products however, there has been a recent shift in research paradigms towards novel formulation strategies to render these agents invaluable complementary treatments. In this view, vitamin D has gained interest, however it’s effective therapeutic use is limited by low aqueous solubility, erratic inter-patient response, and inadequate formulation design. Cholecalciferol (D3), being a potent form of the vitamin, is widely supplemented and prescribed and was selected as the model agent for proof of concept in the design of a novel oral Drug Delivery System (DDS) in the current research. An ideal physiological milieu is often essential for intended performance of even advanced DDS’s. GIT topology may have an even greater impact on modified dosage forms compared to conventional dosage forms. The use of absorption and solubility enhancers is a tried and tested formulation strategy to improve bioavailability and efficacy of drugs with unfavourable physicochemical characteristics. Despite being an integral part of modern formulation design, these bioenhancers may prove only marginally effective in oral delivery unless the physiological state is considered during formulation. It was therefore imperative that the DDS designed in this investigation included measures to mitigate this effect and achieve robust efficacy regardless of the dynamic GIT condition. In addition, most nutraceuticals typically occur as multicomponent products, yet different combined BCS class vitamins may encounter erratic absorption due to differences in solubility and flocculation effects that impede dispersion in aqueous media. It is therefore imperative to formulate and evaluate a DDS containing more than one nutraceutical agent for greater “real-world” relevance instead of a single vitamin DDS formulation that has been pursued in past studies. The current work therefore set out to develop a DDS capable of orally delivering multiple nutraceutical actives and biological constituents from a single formulation framework with modifiable release kinetics and a unified release of synergistic vitamins, with D3 as the focus agent for enhanced oral bioavailability. Few researchers have investigated the use of multiple biological enhancers combined with synthetic carriers in a dosage form to aid nutraceutical deliveryItem Determination of the effect of different blade speeds and mixing times on the homogeneity of mixtures containing different ratios of two powders(2015-04-16) Van Wyk, ElzaanAim The first step in a wet granulation process is dry mixing. This step has the objective of ensuring that all the raw materials are mixed such that the end product is homogeneous. Dry mixing in a high shear mixer instead of a blender saves cost. However, the mixing parameters have not been well researched. Dry mixing parameters that are currently used, have been established through experience, trial and error and in-process testing. Alexander and Muzzio (2006) confirms this by stating that there are currently no mathematical techniques to predict blending behaviour of granular components without prior experimental work; therefore, blending studies start with a small-scale, try-itand- see approach. Even though they are referring to blending, the same is also true for dry mixing. Both processes are the mixing of powders. Therefore the aim of this research was to develop parameters for dry mixing, based on experimental work. Methods Using a Saral rapid mixer and wet granulator (Saral Engineering Company, India), experiments were performed according to a 24 two-level Plackett-Burman Design method, to determine the effects of different blades (mixer/impeller and chopper) speeds and mixing times on the homogeneity of the mixtures containing different ratios of two powders that have different densities and particle sizes. One of the powders mixed, was enalapril maleate. This was chosen as it can be assayed. Samples were taken from the bowl and tested for assay. The mix for a specific experiment is homogeneous if the results of all 7 assayed samples are within 10 % of the target % w/w value and the % Relative Standard Deviation (% RSD) of the 7 results is less than or equal to 5,0 %. The outcome was being measured in % RSD. A lower % RSD indicates a more homogeneous mix. The parameters developed, will be beneficial to pharmaceutical companies as it can assist them to improve accuracy, consistency and quality of granular mixes. The experimental method used can serve as an example for future experiments. Results The results indicated that impeller blade mixing speed and mixing time are the two factors that have the biggest impact on the homogeneity of a mix in a high shear mixer. Chopper blade speed was also found to be significant, but less than the above two parameters mentioned. Optimal parameters were predicted. Conclusion As there are many parameters to be controlled during dry mixing in a high shear mixer, a statistical design method is suitable to establish the parameters that would have the most impact on the end result. Statistically it was found that mixing speed of the main impeller and chopper blades and overall mixing time are the three factors that have the biggest impact on the homogeneity of a mixture. The mixing time and impeller blade speed have proven to be more significant than the chopper blade speed. Concentration was found to be insignificant. For our experiments and for the specific granulator used the following optimal parameters could be deduced: Impeller blade set at 191 rpm, chopper blade set at 2002 rpm and mixing time set at 3.01 minutes.Item A novel antineoplastic nano-lipobubble drug delivery system for passively targeted ovarian cancer therapy(2015-04-13) Frank, Derusha
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